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X Inactivation, Female Mosaicism, and Sex Differences in Renal

Barbara R. Migeon

McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University, Baltimore Maryland

ABSTRACT A good deal of sex differences in is attributable to sex differences expressed only in the testes, they have to do in the function of genes on the . Males are uniquely vulnerable to with testicular function and fertility. With in their single copy of X-linked genes, whereas females are often mosaic, one X chromosome, males have only a sin- having a mixture of cells expressing different sets of X-linked genes. This cellular gle copy of their X-linked genes. mosaicism created by X inactivation in females is most often advantageous, pro- On the other hand, even though fe- tecting carriers of X-linked mutations from the severe clinical manifestations seen males have two copies of these genes, in males. Even subtle differences in expression of many of the 1100 X-linked genes both are not expressed in the same cell. may contribute to sex differences in the clinical expression of renal diseases. Only one X is programmed to work in each diploid somatic cell. All of the other J Am Soc Nephrol 19: 2052–2059, 2008. doi: 10.1681/ASN.2008020198 X chromosomes in the cell become inac- tive during fetal development. Briefly, compensation for X dosage in our spe- Although being female conveys a protec- with normal kidney function. This re- cies is accomplished by a process that en- tive effect on the progression of chronic view addresses the genetic and epigenetic sures only a single X is active in both renal disease, the basis for this sex differ- programs that contribute to the sex dif- sexes. In cells with more than two X ence is not well understood. Little is ferences in renal diseases. chromosomes, all X chromosomes but known about the effects of sex on the de- Without doubt, the clinical manifes- one are silenced. velopment of the kidney. The numbers tations of renal diseases are influenced by In human females, the choice of the of glomeruli are the same for men and X inactivation, the developmental pro- active X chromosome is random so that women, and the greater glomerular vol- gram that equalizes the transcriptional the X inherited from the father has the ume in males is related to the larger size output of X–linked genes in males and same possibility of being active as the X of their kidneys and body surface area.1 females.4 X inactivation is an obligatory inherited from the mother. Silencing of In the absence of structural differences to program, driven by the sex difference in the other X or Xs is mediated by the syn- account for the accelerated progression the numbers of X chromosomes that thesis of a special type of noncoding RNA of renal injury in males, hormonal differ- arose during mammalian evolution. The molecule emanating from the X inactive ences have been implicated. Animal human Y chromosome was created by transcript (XIST) locus on the X chromo- models support the protective effect of destroying one member of the chromo- some.6 Spreading along the chromosome, estrogen on and the some pair that evolved into our sex chro- these molecules modify the underlying nephrotoxic effects of testosterone,2 yet a mosomes. As a result, XX females have chromosome and induce transcriptional great deal of evidence implicates events two X chromosomes, whereas XY males silence. Once silenced, most genes on the occurring during embryonic develop- have only one. The DNA sequence of the ment. The effect of poor nutrition and human X chromosome reveals about other maternal factors leading to low 1100 genes, an eclectic group, encoding Published online ahead of print. Publication date birth weight can reduce the numbers of proteins needed for almost all of our available at www.jasn.org. nephrons in the developing kidney,3 but body functions, some having to do with Correspondence: Dr. Barbara R. Migeon, McKu- the effect is the same for males and fe- sex but most involving nonsexual activi- sick-Nathans Institute of Genetic Medicine, 459 5 Broadway Research Building, 733 N. Broadway, Bal- males. What is generally ignored in any ties. In contrast, the genes on the Y chro- timore, MD 21205. Phone: 410-955-3049; Fax: 410- discussion of sex differences in renal dis- mosome are far less diverse. Although a 614-8600; E-mail: [email protected] ease are the relevant genes on the X chro- few share functions with their X-linked Copyright ᮊ 2008 by the American Society of mosome, which when mutated interfere counterpart, most are unique to the Y;

2052 ISSN : 1046-6673/1911-2052 J Am Soc Nephrol 19: 2052–2059, 2008 www.jasn.org BRIEF REVIEW inactive X usually remain mute in all when one of the X-linked alleles is mutant ized regions of the ureteric bud by small daughter cells, so that the inactivation pat- and the other is normal. However, in fact, groups of cells that communicate with ad- tern is clonally inherited.7 the comingling of cells synthesizing differ- jacent groups of cells, all of this under the As a consequence of clonal inheritance ent X-linked proteins, whether normal or control of a variety of transcription and of the inactive X, human females are mo- abnormal proteins, is responsible for a other signaling factors. And the develop- saics, a composite of two populations of functional diversity not seen with most au- ment of glomeruli requires interactions be- cells that differ as to which X chromosome tosomal genes. Males with only a single tween epithelial cells and infiltrating endo- is expressed. This mosaicism would be copy of their X-linked genes are at a disad- thelial cells. What is not known is the meaningless if the alleles on maternal and vantage as they have less diversity and are nature of the sex differences in this process. paternal X chromosomes were identical as vulnerable to the effects of mutations at a There are bound to be sex differences be- they are in inbred laboratory mice; how- large number of loci, including those cause of the cellular mosaicism resulting ever, we, as a species, are so heterozygous shown in Table 1. It is this cellular mosa- from X inactivation. Also not known is the that females are indeed mosaic for a good icism that provides biologic advantage to mosaic composition of the kidney. Do the number of their X-linked alleles. The size females carrying mutations responsible for different cells that communicate to induce of the mosaic patch differs from tissue to in males. the kidney express the same or different pa- tissue.8 It is very large in the where rental X chromosomes? The onset of X in- all of the cells within a chorionic villus have Sex Differences in Renal activation is timed with the differentiation the same active X, and very small in the Development events that give rise to the various tis- brain with a great deal of comingling of the The development of the kidney is intricate sues11,12; therefore, in the kidney, it might two types of cells. The phenotype of any cell because of its architectural complexity. coincide with the earliest events in renal is determined not only by the allele it ex- The entire urinary collecting system starts differentiation. Clearly, the time when X presses, but also by the interactions with as an outgrowth of the Wolffian duct and inactivation occurs precedes the time when those neighbors, expressing the other al- forms by a complex process of branching the kidney is completely formed in hu- lele. Such interactions are best seen and remodeling.9,10 According to Costan- mans. From what is known about develop- through the window of disease, that is, tini,10 branching may be initiated in local- ment of the mouse kidney, most nephro-

Table 1. Sex differences in renal manifestations of X-linked diseases affecting the kidney Mutated Male Renal Disease OMIM# X Mapa Female Renal Phenotypeb Gene Phenotypeb 301050 Xq22.3 COL4A5 ; glomerulitis; Some ; rarely ESRD Leiomyomatosis with 308940 Xq22.3 COL4A5 & hematuria; ESRD nephropathologyc COL4A6 Dent disease 1 300009 Xp11.22 CLCN5 Progressive proximal tubular Usually asymptomatic; Nephrolithiasis 310468 Xp11.22 CLCN5 disease; ESRD; hypercalciuria; occasionally and Hypophosphatemic rickets 300554 Xp11.22 CLCN5 nephrolithiasis; proteinuria; hypercalcinuria recessive hypophosphatemic rickets Low molecular weight 308990 Xp11.22 CLCN5 proteinuria Dent disease 2 300555 Xq26.1 OCRL Proteinuria; aminoaciduria; Usually asymptomatic; some Lowe’s syndrome 309000 Xq26.1 OCRL phosphaturia aminoaciduria 301500 Xq22 GLA Cytoplasmic inclusions, Less severe inclusions; proteinuria, ESRD occasionally ESRD Hypophosphatemic rickets 307800 Xp22.1–2 PHEX Hypophosphatemia; More variable and less severe dominant (vitamin D resistant) Lesch-Nyhan syndrome 300322 Xq26–27.2 HPRT Uric acid stones, nephropathy, Usually none and renal obstruction Nephrogenic 304800 Xq28 AVPR2Ϫ Excessive diuresis Milder symptoms if any insipidus Syndrome of inappropriate 300539 Xq28 AVPR2ϩ Gain of function: hyponatremia, Variable, but usually less severe antidiuresis systolic hypertension Oral facial digital 311200 Xp22.2 OFD1 Fetal death Polycystic disease, ESRD syndrome 1 ESRD, End-stage renal disease. aLocation of the gene on the X chromosome. bHemizygous male and heterozygous female. cContiguous gene syndrome with large deletions.

J Am Soc Nephrol 19: 2052–2059, 2008 Sex Differences in Renal Diseases 2053 BRIEF REVIEW www.jasn.org genic and glomerular development occurs cells. Usually, the distribution of the two bolic cooperation through gap junctions, after the onset of X inactivation. mosaic populations is expected to be endocytosis, and other intercellular Also unknown is the number of pro- random, following a bell-shaped curve channels. If gene products cannot be genitor cells giving rise to the mature kid- around a mean of 50%. But some women shared, then normal cells may outgrow ney, and the size of the mosaic patches may have very skewed patterns of X inac- the mutant ones and eventually elimi- along the nephron and in the glomerulus. tivation because of the small numbers of nate them. Such strategies are carried out Because most of the kidney is formed after cells present when X inactivation occurs, in a tissue-specific fashion; those tissues the onset of X inactivation and because or mutations affecting XIST, or a growth unable to metabolically cooperate may branches may consist of clonal populations advantage of one of the cell populations. undergo cell selection instead. These in- of cells, the patch size might be relatively In the case of carriers of mutations affect- teractions, occurring uniquely in females, large. In cell culture,13 a human renal cell ing the kidney, the nature of the cellular ameliorate their phenotype so that they can yield progeny of different morphologic mosaicism will determine whether or not may have no clinical manifestations at all. types, and clones give rise to rather compli- she has significant renal disease. In any Cell-to-cell transfer of gene products cated structures. Although the clonal basis case, the X chromosome mosaicism, masks the genotype, as the mutant cells of kidney development has not been eluci- even if it were not responsible for sex dif- are no longer deficient. Good examples dated, some insights come from studies of ferences in kidney development, is are mutations affecting the metabolism females who carry mutations affecting the clearly responsible for sex differences in of large intracellular proteins. The en- kidneys (see Alport Syndrome section and renal diseases. zymes needed to digest such molecules Figure 1). can be transferred from one cell to an- It is likely that a woman’s kidney is Sex Differences in Renal Disease other by mannose-6 phosphate-medi- composed of two populations of cells dif- Table 1 shows the sex differences in ex- ated endocytosis. Without sufficient en- fering in the X-linked alleles that are ex- pression of some diseases that affect the zyme, the undigested proteins can pressed. The two kinds of cells comingle kidney; most affect predominantly males induce kidney disease, which is the case at least to some extent and cooperate and have variable penetrance in carriers. in Fabry disease. metabolically, or in other ways. Such in- The list is not exhaustive, and it consists termingling of cells will determine the ul- mainly of syndromes associated with se- Fabry Disease timate phenotype of her mosaic renal vere deficiencies of the gene products. The lysosomal enzyme alpha galactosidase The reference numbers for the On-line A (GLA) is ubiquitously expressed, as it is Mendelian Inheritance of Man (OMIM) needed to break down glycosphingolipids are included as a source of further infor- present in most cell membranes. In the ab- mation. There are more OMIM numbers sence of sufficient enzyme, the glycosphin- than the number of mutant genes be- golipids accumulate and plug the blood cause the syndromes were described be- vessels in all tissues, producing severe epi- fore the genes were known. The identifi- sodic pain and premature death. cation of mutations has led to a broader The severe kind of renal disease oc- appreciation of the spectrum of disor- curs most often in males, who usually re- ders attributable to mutations in a single quire enzyme replacement therapy with gene. Some of the phenotypic variations human recombinant GLA and kidney are the result of different effects of mul- transplants for end-stage renal disease tiple mutations within the same gene. (ESRD). In the kidney, the glycosphin- Generally, the sex differences in the golipids colocalize with the lysosomes manifestations of X-linked diseases fall and are deposited in the glomeruli, renal into two categories: Either males have a tubules, and blood vessels. Fabry ne- disease, and females have no manifesta- phropathy consists of glomerular sclero- tions or attenuated manifestations, or fe- sis, tubular fibrosis, and hyalinization of males uniquely manifest the disease be- the blood vessels. Clinically, the renal cause the is lethal in males. disease manifests as hypertension, mod- Carriers with the same mutation survive erate proteinuria, lipiduria, and micro- because enough of their cells express the scopic hematuria. normal allele to carry out the function of Many heterozygous females manifest Figure 1. Cellular mosaicism in a glomer- ulus (B) from a female, heterozygous for the gene, or the gene product can be some signs of the disease, but in an atten- X-linked Alport syndrome, and (A) normal transferred from normal to deficient uated form. These affected females usu- control. Specimens stained for the ␣5(IV) cells. Sharing of gene products takes ally have a later onset of symptoms, live chain. Adapted from reference place in the usual ways that cells commu- significantly longer, and their symptoms 19, with permission. nicate with each other, namely, meta- can be more easily relieved by enzyme

2054 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 2052–2059, 2008 www.jasn.org BRIEF REVIEW replacement than males. In any case, the for the reutilization of breakdown prod- in monozygotic twins suggests that twin- symptoms and circulating levels of GLA ucts of DNA, specifically the purine bases ning can trigger skewed X inactivation.18 are more variable in females, and the dis- (hypoxanthine and guanine). In addi- The severe HPRT deficiency in manifest- ease has a slower rate of progression. tion to mental retardation and spastic ce- ing females results from at least two events: Clearly, the milder renal disease is the re- rebral palsy, severe HPRT mutations re- mutation in one HPRT allele along with sult of the effect of having cells that pro- sult in uric acid deposits in joints and nonrandom inactivation of the X chromo- duce normal amounts of GLA. Also, the kidney. Less severe HPRT mutations in some carrying the normal allele. normal cells can export the enzyme by males usually produce only gout and kid- endocytosis to the mutant cells, thereby ney stones (the Kelley-Seegmiller syn- Alport Syndrome ameliorating their deficiency. Enzyme drome, OMIM #300323). However, in Alport syndrome is a group of hereditary transfer is enough to preclude elimina- some cases, they also result in ESRD, of- diseases affecting the kidney that may tion of mutant cells but inadequate to ten unrecognized because of the lack of also cause and ocular le- correct the defect, which explains why other symptoms. These boys and others sions. In the kidney, there is hematuria heterozygotes may be symptomatic. The who are treated with allopurinal for a and proteinuria, often leading to ESRD. GLA enzyme is taken up poorly com- long time may also develop xanthinuria The molecular defects involve the base- pared with other lysosomal enzymes, and xanthine urolithiasis with staghorn ment membranes of both tubules and perhaps explaining why almost all carri- calculi.16 glomeruli, most often caused by defi- ers have the lens opacities characteristic On the other hand, women, heterozy- ciency of one of their type IV collagen of Fabry disease. Generally benign, their gous for severe Lesch-Nyhan mutations, components. Approximately 85% of Al- presence suggests that having 50% nor- even though they have deficient cells in port syndrome results from mutations in mal cells is not enough to prevent all many tissues, manifest none of these the X-linked COL4A5 collagen gene manifestations of this disease.14 symptoms, not even gout. In many of (XLAS). Males with a COL4A5 defi- Approximately 10% of Fabry carriers their tissues, inosinic acid, the product of ciency almost always end up with ESRD, eventually undergo or kidney the HPRT metabolic reaction, is trans- whereas females have a wide range of transplants, usually because such “man- ferred from the normal to the mutant phenotypes ranging from asymptomatic ifesting” heterozygotes have significantly cells by means of gap junctions. Con- to disease as severe as that of males.19 Ac- more mutant than wild-type cells, re- necting the cytoplasms of neighboring cording to Kashtan,19 as many as 25% of flecting skewed rather than random pat- cells, these channels mediate the transfer carriers may have severe renal disease, terns of X inactivation. In this case, the of small molecules, such as inosinic acid, but their disease usually begins later than skewing is not the result of a growth ad- across the lipid bilayer of the cell mem- in males. Attempts to correlate the phe- vantage of the mutant cells but reflects branes. However, in blood cells (both notype of carriers with their X inactiva- instead stochastic events, or skewing for erythroid and leukocytic lineages), tion patterns in blood cells have been reasons unrelated to the mutant gene, which lack gap junctions (and hence the generally unsuccessful. This is expected, such as chromosome abnormalities and ability to transfer inosinic acid), the mu- as the blood cells are not affected by these twinning.7 The effect of skewed X inacti- tant cells have a growth disadvantage and mutations. Kashtan and colleagues stud- vation on phenotype is most evident in are completely eliminated after the first ied the glomeruli of human females with the occasional carrier (approximately 1 decade of life.7 COL4A5 mutations and female mice car- in 200) that fully manifests Fabry syn- At least seven females are reported to rying a human Alport mutation.20 Figure drome. In these cases, the affected female have the full biochemical and clinical 1B shows a glomerulus from a human has only mutant cells, reflecting severe manifestations of the syndrome.17 All are Alport heterozygote immunolabeled skewing (Ͼ95% mutant cells). The influ- heterozygous for an HPRT mutation, but with an antibody to COL4A5. Striking is ence of X inactivation is striking in a pair of their normal allele is never transcribed the mosaic pattern in the kidney, with a female MZ twins, who are uniquely prone because it is always on the inactive X. block of labeled cells, most likely normal to skewing. Only one twin had the classic One girl, presenting with acute renal fail- clone(s), and blocks that are not labeled, form of Fabry disease, and her cells pre- ure at the age of 2 months, had only mu- most likely mutant clone(s). In mice, the dominantly express the mutant allele.15 tant cells because of a balanced X/auto- pattern varies, with some glomeruli some translocation with a breakpoint more labeled than others,20 suggesting Lesch-Nyhan Syndrome within the HPRT gene creating the mu- that each glomerulus is composed of The kidney disease in males with Lesch- tation. As happens in such cases, the progeny of several progenitor cells, and Nyhan mutations is most often acute re- translocation chromosome is always the are often mosaic with respect to base- nal failure caused by crystal nephropa- active X, so the mutation is expressed in ment membrane function. In the case of thy. These boys have an almost complete all her cells. Another affected female is an COL4A5 mutations, the deficiency is cell deficiency of the enzyme hypoxanthine identical twin with mostly mutant skin autonomous. However, one could imag- phosphoribosyl transferase (HPRT), cells; her normal co-twin had no skew- ine that other gene products might be which is needed, especially in the brain, ing. The discordant phenotype observed passed between glomerular cells. The

J Am Soc Nephrol 19: 2052–2059, 2008 Sex Differences in Renal Diseases 2055 BRIEF REVIEW www.jasn.org availability of female mice with the Al- also have hypercalciuria and nephrocalci- males, and in one case this was explained port mutation provides the means to de- nosis, resulting in renal stones, and some by severe skewing such that only mutant termine how much of a glomerulus have hypophosphatemic rickets. The dis- cells were present, with her normal allele needs to be functional and how many ease is the result of inactivating muta- mute on her inactive X.29 normal glomeruli are needed for ade- tions of CLCN5, encoding a member of quate renal function. the CLC family of voltage-gated chloride Oral Facial Digital Syndrome Type 1 The COL4A5 gene is located in the channels and transporters. CLCN5 local- The syndrome, characterized by malfor- middle of the long arm of the X, not close izes to endosomes of the proximal tu- mations of the face, oral cavity, and dig- to the pseudoautosomal region that is bule. In the absence of CLCN5, there are its, affects primarily females because af- homologous on X and Y chromosomes— less of the scavenger protein receptors, fected males die in utero. Polycystic where the genes are expressed from all sex megalin and cubilin, in the proximal tu- kidneys are found in up to half the cases, chromosomes. Some X-linked genes in bules, where they are needed to take up especially when the OFDI mutation af- other regions of the X are said to escape low molecular weight proteins from the fects a splice site.30 The protein encoded inactivation as they are expressed from the glomerular filtrate. Because random in- by the gene (OFD1 protein) is located in inactive X to some extent21; their expres- activation provides enough normal cells, the centrosome of the basal body of pri- sion is limited because the chromatin of all females are usually asymptomatic, but mary cilia. Deficiency of the protein causes but the pseudoautosomal region is quite some may have hypophosphatemia and ciliary dysfunction, resulting in early devel- repressed. The COL4A5 locus has not been decreased urine osmolality. opmental defects in the heart, neural tube, studied directly; however, the unlabeled kidney, and affecting laterality because of cells in glomeruli (Figure 1) suggest there is Dent 2 Disease (Lowe Syndrome) absent cilia in the embryonic node. little expression of COL4A5 from the inac- Another cause of renal tubular dysfunction The severity of the polycystic renal tive X. Severe skewing that by chance fa- is Lowe oculocerebrorenal syndrome, disease in heterozygous females varies vors the mutant allele has been observed in which affects multiple tissues and organs. widely, and undoubtedly their X inacti- kidney cells from a heterozygote, manifest- The culprit is OCRL1, an X-inked gene en- vation status plays a role in determining ing severe renal disease.22 coding inositol 5-phosphatase enzyme lo- how severe it will be.31 From studies of A subset of patients with Alport syn- cated in the Golgi complex, now called the OFDI gene in cultured fibroblasts, we drome has disseminated smooth-muscle OCRL enzyme.24 The lack of this phospha- know it is expressed to some extent from tumors of the esophagus, large airways, tase causes and abnormal neuro- the inactive X,21,32 most likely because of and female reproductive tract. In these logic and renal function by interfering with its telomeric location (Xp22.3). It is cases, the mutation is a deletion encom- Golgi vesicular transport. Lowe syndrome likely that human heterozygous females passing not only COL4A5 but its neigh- is also called Dent 2 disease because the are protected to some extent by the small bor COL4A6 as well (Table 1). Females mechanism of kidney disease is similar to amount of protein produced from the with one copy of the deletion manifest that of Dent 1 disease. In both cases, the normal allele on their inactive X. In mice, the smooth-muscle tumors as often as renal tubules lack the receptors that con- the gene on the inactive X is completely males do, but their renal disease tends to trol the exchange of certain small mole- silent, and all affected females have poly- be milder with only rare females affected cules between the urine and the blood. cystic kidneys, surviving only a short with ESRD. Although not tested, pre- OCRL attaches itself to an adaptor mole- time after birth. In any case, along with sumably such females are the ones with cule, involved in the sorting and signaling variation in the nature of the mutation, greater numbers of mutant cells in their of cell surface receptors in the brain and the variability either in expression from kidneys. As a result of a severe growth kidney. In the kidney, that receptor protein the inactive X or in the number of nor- disadvantage during embryogenesis, is megalin, just as in Dent 1 disease.25 mal cells clearly explains the variability in most deleted X chromosomes are inac- Historically, Lowe syndrome was de- renal disease among carriers. Some may tive in every cell, but these Alport dele- fined as only affecting boys, in whom it have sufficient OFD1 protein for cilium tions are apparently not large enough to causes more frequent cataracts, rickets, assembly. Because the homologous locus influence the growth of the mutant cell. and tubular proteinuria than seen in on the Y chromosome is a nonexpressed If they were, then the deleted X would Dent 1 disease.26 Female carriers are usu- pseudogene, affected males cannot ben- always be inactive, and the mutation ally asymptomatic, but most of them, efit from the allele on their Y chromo- would not be expressed at all. like carriers of Fabry disease, have lens some. It is likely the leaky expression of opacities that do not cause visual prob- the normal allele from the inactive X Dent 1 Disease lems.27,28 This suggests that the lens is weakens the influence of X inactivation Dent disease is an X-linked disorder that particularly sensitive to mutations in the on the severity of the polycystic disease. usually affects males. Mutations are al- heterozygous state. In any case, lens Studies show that 7 of 23 patients had most always associated with low-molec- opacities provide a rather sensitive assay skewing, but in none was it extreme ular weight proteinuria, aminoaciduria, for heterozygotes in both diseases. A few (Ͼ90%), and neither the normal nor and progressive renal failure.23 Most males Lowe heterozygotes are fully affected as mutant allele was favored.30

2056 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 2052–2059, 2008 www.jasn.org BRIEF REVIEW

Nephrogenic rogenic syndrome of inappropriate antidi- Other X-Linked Diseases With a requires a fine uresis.37 Originally reported in male infants Role in Kidney Development balance between to bring water only, a few adults have been identified. Af- In the case of the mutations in X-linked into the body and the release of antidi- fected males have systolic hypertension genes known to be involved in the differ- uretic hormone () to mini- and spontaneous episodes of hyponatre- entiation and function of the kidney, mize water loss. Diabetes insipidus is a mia, whereas the carriers are usually most affect renal function directly disease of water homeostasis resulting asymptomatic, but some have mild poly- through deficiency of receptors and from failure to concentrate urine.33 Al- dipsia and abnormal water-load tests.37,38 other structural elements, or indirectly though some cases can be central in ori- through nephrolithiasis or renal obstruc- gin because of an insufficient production Hypophosphatemic Rickets tion. Males usually bear the brunt of the of vasopressin, most are caused by an im- X-linked hypophosphatemia, also problem. Most females have far less se- paired renal response to vasopressin. Ap- known as vitamin D resistant rickets, is a vere abnormalities than males with the proximately 90% of the patients with disorder of phosphate homeostasis same mutation. The only female-specific nephrogenic diabetes insipidus (NDI) caused by mutations at the PHEX locus disorder is X-linked polycystic disease are boys with mutations in the X-linked that produce defects in the renal reab- because males do not survive gestation. gene encoding the arginine vasopressin sorption of filtered phosphate and in the The lack of other X-linked developmen- receptor 2 (AVPR2); the rest have an au- metabolism of vitamin D. Clinically, X- tal disorders of the kidneys no doubt re- tosomal NDI, caused by mutations in the linked hypophosphatemia manifests as flects the fact that mutations in X-linked gene encoding the -2 water defective mineralization of growth plates genes expressed in the kidney interfere channel. Most of the AVPR2 mutations (rickets) and (osteomalacia).39 with the development of other organs as result in V2 receptors that cannot reach Many patients have ultrasonic evidence well. For example, the Simpson-Golabi- the plasma membrane because they are of nephrocalcinosis. The gene belongs to Behmel syndrome (OMIM 312870), trapped within the renal cell. Affected the family of endopeptidases that de- producing large dysplastic kidneys along males have excessive thirst and produce grade or activate a variety of peptide hor- with congenital heart defects, spleno- large quantities of dilute urine, even when mones. PHEX is expressed in bone, megaly, cryptorchidism, and hypospa- treated with exogenous vasopressin. rather than in the kidney, suggesting that dias, is caused by a mutation in the Glypi- Because most patients are males, the the renal abnormalities are secondary to can-3 gene at Xq26. Almost all of the few affected females are usually consid- the skeletal defect.39 reported individuals are male, but some ered to have a mutation in the autosomal Males usually have overt bone manifes- female relatives have minor malforma- gene. However, van Lieburg et al.,34 who tations, whereas females tend to have a tions. The rare manifesting females have described three NDI families in which fe- wider range of bone disease, from severe to disruptions in the gene from X-auto- males had classic features of the disease, none at all. Also, affected females have a some translocations that also caused considered the possibility that some higher rate of tubular phosphate reabsorp- skewed X inactivation.42 could be the result of AVPR2 mutations. tion than affected males. However, serum Because the development of the kid- They suggested that the manifesting fe- phosphate levels are similar in both sexes ney is a multifactorial process, many males had too many mutant cells because and do not differ in homozygous mutants, gene products contribute to the end re- of skewed X inactivation. This hypothe- hemizygous males, or heterozygotes. No sult. Therefore, it is not surprising that sis was tested by Nomura et al.,35 who one has yet compared the levels of mRNA mutations in more than one gene may be reported two related heterozygous fe- encoding PHEX in bone cells where PHEX needed to produce developmental prob- males with clinical disease. Both mani- is predominantly expressed, a more direct lems of the urinary tract, especially if the festing females had skewed X inactiva- assay for gene dosage effects. The locus mutations produce partial deficiencies. tion in blood cells; the most severe had maps to the tip of the human X chromo- None may be detrimental alone but, in the greatest amount of skewing. The some where genes may escape inactivation. collaboration, are sufficient. Mutations skewing responsible for the variable de- Studies of hybrid cells21 suggest that there in the gene encoding the angiotensin II grees of and is not may be some leaky expression from the in- receptor, type 2 (AGTR2) (OMIM attributable to a growth advantage of ei- active X in some individuals, but the level 300034) are implicated in the develop- ther normal or mutant cell. Of interest, a of expression is not known. X inactivation ment of uteropelvic junction stenosis or heterozygous female developed transient studies of blood samples from 12 carriers atresia. Mice carrying a null allele for X- NDI associated with decreased AVPR2 did not show any skewing.40 The inac- linked AGTR2 have phenotypes that re- for the first time at the age of 55 when tivation status of the mouse PHEX gene semble congenital anomalies of the hu- undergoing the stress of a surgical proce- is also unknown, but the availability of man kidney and urinary tract. These dure. Approximately 80% of her blood heterozygous mice carrying a condi- mice lack other somatic anomalies, and cells were of the mutant type.36 tional deletion of the PHEX gene in os- inheritance does not follow a typical A gain-of-function mutation (R137C) teoblasts and osteocytes should shed mendelian pattern.43 AGTR2 has a role in in the AVPR2 gene also produces the neph- light on such issues.41 apoptosis, which is essential for eliminat-

J Am Soc Nephrol 19: 2052–2059, 2008 Sex Differences in Renal Diseases 2057 BRIEF REVIEW www.jasn.org ing mesenchymal cells surrounding the that affect T lymphocytes can increase REFERENCES Wolffian duct and . Nishimura et al. their transcriptional output and may speculate that delayed apoptosis may cause contribute to the striking female predi- 1. Neugarten J, Kasiske B, Silbiger SR, Nyen- gaard JR: Effects of sex on renal structure. 43 the diverse anatomic abnormalities. lection of this disease. Nephron 90: 139–144, 2002 Males with AGTR2 mutations also have X- 2. Neugarten J: Gender and the progression of linked mental retardation. No females Conclusion renal disease. J Am Soc Nephrol 13: 2807– have been ascertained, but then, only males The single active X chromosome is re- 2809, 2002 are usually studied. On the other hand, sponsible for sex differences in kidney 3. 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